Nickel Sensitivity Is Associated with GH-IGF1 Axis Impairment and Pituitary Abnormalities on MRI in Overweight and Obese Subjects.

Renata Risi,Rossella Tozzi,Lucio Gnessi,Alessandra Caputi,Stefania Mariani,Eleonora Poggiogalle,Carla Lubrano,Davide Masi,Mikiko Watanabe,Simonetta Masieri,Elena Gangitano

doi:10.3390/ijms21249733

Renata Risi, Rossella Tozzi + Show 9 more

Open Access

https://doi.org/10.3390/ijms21249733

Copy DOI

Abstract

Nickel (Ni) is a ubiquitous metal, the exposure of which is implied in the development of contact dermatitis (nickel allergic contact dermatitis (Ni-ACD)) and Systemic Ni Allergy Syndrome (SNAS), very common among overweight/obese patients. Preclinical studies have linked Ni exposure to abnormal production/release of Growth Hormone (GH), and we previously found an association between Ni-ACD/SNAS and GH-Insulin-like growth factor 1 (IGF1) axis dysregulation in obese individuals, altogether suggesting a role for this metal as a pituitary disruptor. We herein aimed to directly evaluate the pituitary gland in overweight/obese patients with signs/symptoms suggestive of Ni allergy, exploring the link with GH secretion; 859 subjects with overweight/obesity and suspected of Ni allergy underwent Ni patch tests. Among these, 106 were also suspected of GH deficiency (GHD) and underwent dynamic testing as well as magnetic resonance imaging for routine follow up of benign diseases or following GHD diagnosis. We report that subjects with Ni allergies show a greater GH-IGF1 axis impairment, a higher prevalence of Empty Sella (ES), a reduced pituitary volume and a higher normalized T2 pituitary intensity compared to nonallergic ones. We hypothesize that Ni may be detrimental to the pituitary gland, through increased inflammation, thus contributing to GH-IGF1 axis dysregulation.

Highlights

Obesity is a growing health problem that has reached epidemic proportions and has led to a skyrocketing increase in the prevalence of many of its complications, some of which are well established, namely diabetes mellitus type 2, cardiovascular disease, obstructive sleep apnoea syndrome (OSAS), non-alcoholic fatty liver disease (NAFLD) and sarcopenia [1,2,3,4,5], and others are currently being further investigated [6,7]
Occupational exposure to Ni and its compounds in sensitized individuals can cause allergic dermatitis known as nickel allergic contact dermatitis (Ni-ACD), the most common cutaneous delayed-type hypersensitivity reaction worldwide; Ni-ACD prevalence in the general population is 8–18% in the US and Europe, and it is estimated to reach 16% in southern European countries such as Italy [25,26]; Ni allergy may manifest as Systemic Ni Allergy Syndrome (SNAS), a condition occurring in a considerable number of patients sensitized to Ni and characterized by cutaneous and extracutaneous signs and symptoms [27]
Ni allergy is much more common in patients with obesity compared to the general population [35], and it is even more widespread among obese patients with worse metabolic profiles [36]; obese patients sensitized to Ni have a significantly lower baseline insulin-like growth factor 1 (IGF-1) level and a blunted growth hormone (GH) dynamic response compared to nonallergic ones [36]

Summary

Introduction

Obesity is a growing health problem that has reached epidemic proportions and has led to a skyrocketing increase in the prevalence of many of its complications, some of which are well established, namely diabetes mellitus type 2, cardiovascular disease, obstructive sleep apnoea syndrome (OSAS), non-alcoholic fatty liver disease (NAFLD) and sarcopenia [1,2,3,4,5], and others are currently being further investigated [6,7]. The contribution of Ni allergy to fat mass excess could be immune-mediated, since both SNAS [37] and obesity [38] share an enhanced systemic inflammatory response as a fundamental pathogenetic mechanism; it is known that exposure to different metals, such as Ni, can act as a trigger of autoimmune disorders, eventually leading to neurotoxicity [39]. Studies on animals and human subjects have prospected that Ni could exhibit endocrine-disrupting activity, being able to alter normal synthesis and/or secretion of GH [46,47,48,49] In this scenario, it is worth recalling that fat mass excess is associated with profound structural changes of neurons and glia in the hypothalamus [50] and with the presence of Empty Sella (ES), a complex condition which may eventually lead to hypopituitarism and, in particular, to adult-onset GH deficiency (GHD) [51]. Excessive exposure to some metals might result in their brain deposition, often leading to specific MRI findings

Methods

Results

Discussion

Conclusion